Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemic injury. Our published data indicate that up to 50% of sickle cell patients have vascular dysfunction due to impaired bioavailability of endogenous nitric oxide, due in large part to scavenging of nitric oxide by cell-free hemoglobin. We recently have completed studies that directly demonstrate endothelial dysfunction in patients with sickle cell disease, characterized by decreased ACh dependent vasorelaxation in forearm blood flow studies, distinct from the nitric oxide resistance above. Further, we have found in sickle cell patients a new association between low levels of apoA-I, pulmonary hypertension and endothelial dysfunction. Raising levels of HDL and therefore apoA-1, could have the effect of ameliorating the endothelial dysfunction characteristic of sickle cell disease by affecting endothelium dependent vasorelaxation. Therapies directed at restoring HDL in these patients may be beneficial. HDL is thought to promote vascular health in a variety of ways, some of which are unrelated to lipid transport. One of the best-known mechanisms relates to efflux of cholesterol from atherosclerotic plaque, yet HDL is thought to have several antithrombotic and anti-inflammatory effects. In vitro HDL attenuates formation of oxidized LDL and inhibits endothelial cell expression of inflammatory cell adhesion molecules. It is also thought to mediate NO production via stimulation of eNOS5, thereby modulating endothelial function. In a study of subjects with atherosclerosis, low HDL levels correlated with impaired vasomotor relaxation via brachial artery FMD. Another study utilizing recombinant HDL cholesterol infused into brachial arteries of hypercholesterolemic men resulted in increased acetylcholine mediated blood flow that was inhibited by the infusion of L-NAME, an eNOS inhibitor, suggesting that HDL increased blood flow via an eNOS dependent mechanism. This may have implications not only for subjects with atherosclerosis, but also for those with sickle cell disease and endothelial dysfunction. We propose that niacin therapy could improve vascular reactivity in response to acetylcholine. Several options for increasing HDL levels have been previously utilized in forearm flow studies using venous occlusion plethysmography or flow-mediated dilation. Reconstituted HDL (rHDL), apoA-1 mimetics and niacin therapy were all shown to improve endothelial dysfunction, and proved safe and effective. This trial will aim to 1) establish the effects of niacin treatment on raising HDL levels in subjects with sickle cell disease, 2) investigate whether niacin treatment would result in improvement of endothelial-dependent relaxation via venous occlusion plethysmography, and 3) compare the efficacy of peripheral arterial tonometry measurements to venous occlusion plethysmography and flow-mediated dilation as indicators of vascular dysfunction. All volunteer subjects will undergo screening with screening history for inclusion/exclusion criteria and baseline laboratory testing including documentation of sickle cell phenotype and apoA-1 or HDL-C level. In order to increase the likelihood that subjects will have endothelial dysfunction at study entry, we will attempt to recruit subjects found to have a lower than average apoA-1 level or a low HDL-C level. Target enrollment is 60 subjects to provide 40 completed studies with 20 subjects randomized to treatment with extended releaase niacin and 20 randomized to placebo drug (stratified to achieve equal representation of men and women). At the initial study visit subjects will undergo a complete history and physical exam, laboratory testing, six-minute walk evaluation, echocardiography, forearm blood flow measurements, flow mediated dilation testing (FMD) and peripheral arterial tonometry (PAT) testing. The subjects will then be randomized to begin a course of extended release niacin therapy or placebo. Subjects and practitioners will be blinded to which subjects are randomized to therapy vs. placebo. Subjects will be asked to refrain during the 3 months of study participation, from the use of any nutritional supplement that contains Niacin as an ingredient on its label. Niacin fortified foods will be permissible. Scheduled follow up clinic visits will occur every two weeks, consisting of a medical history and pill counts. At the four and eight week visits, we will also perform laboratory testing, flow mediated dilation testing, peripheral arterial tonometry testing, and six minute walk testing. For any subjects with ALT levels above normal, ALT will be checked at every visit. The medication dosage will be increased at the four and eight week visits. The study medication will be stopped 48-72 hours before each peripheral arterial tonometry, flow mediated dilation, and forearm blood flow measurement. Upon completion of the 12-week course of niacin or placebo, subjects will return for repeat forearm blood flow measurements, flow mediated dilation testing, peripheral arterial tonometry testing, history and physical exam, six minute walk, echocardiography, and laboratory tests. If needed for scheduling purposes, the study drug may be continued for 1-2 additional weeks. If the subject is hospitalized at a site other than the clinical center for vaso-occlusive pain crisis or other illness during the study, preferably the study medication will be continued at the same dose for 1-2 additional weeks until the subject could be seen at the NIH Clinical Center to verify that it is appropriate to increase the dose.